The principal objective of the proposed research is to obtain quantitative information in vivo concerning the effect of pulmonary fibrosis and pulmonary edema on lung permeability to drugs. By using paraquat-induced lung fibrosis and alpha-naphthylthiourea (ANTU)-induced pulmonary edema as animal models in the rat, pulmonary absorption rates will be measured in vivo for a variety of compounds with different physico-chemical properties and compared in normal and experimentally damaged lungs. To measure pulmonary absorption, 0.1 ml of drug solution is administered through a tracheal cannula into the lungs of anesthetized animals. After various times, lungs are removed and assayed for unabsorbed drug. By plotting the percentage of the dose unabsorbed against time, curves are provided from which may be calculated absorption half-times (t 1/2) and rate constants (K). Comparison of these values obtained in normal (control) animals and animals with pulmonary fibrosis and edema will provide quantitative information regarding the effect of increased interstitial tissue and fluid on the porosity, lipoid nature and transport-dependent energy- producing processes of the air-blood barrier. In addition, rates of drug accumulation by fibrotic and by edematous lungs will be measured in vivo in rats given an i.v. injection of certain drugs used clinically in the treatment of respiratory tract disease (e.g. antibiotics, corticosteroids, antitubercular agents, etc.). At various times after drug administration, lungs will be removed and assayed for the amount of compound present. From graphic plots of amount of drug present in the lungs v. time, accumulation and elimination half-times and rate constants may be calculated. Comparison of these values obtained for normal (control) and damaged lungs will provide additional quantitative data concerning the effect of fibrosis and edema on the pulmonary disposition of parenterally administered drugs.